This LEAD Award proposal is an integrated project designed to test the hypothesis that late onset Alzheimer's Disease (LOAD) is genetic and to identify the genetic loci for LOAD and early onset familial AD (EOAD). EOAD is linked to anonymous DNA probes on chromosome 21 so that experiments designed to identify and describe the genetic locus will focus on chromosome 21 specific expression differences in EOAD. A clinical genetic ascertainment and family development program for EOAD and LOAD is described. Sib-pair screening and standard likelihood analyses are presented. Subtraction hybridization (using tissue available from the Duke Alzheimer's Disease Research Center Rapid Autopsy Protocol), candidate gene analyses, chromosome mapping techniques, and other molecular genetic strategies to define the chromosome 21 gene locus for EOAD and a putative gene(s) for LOAD are described. The LEAD proposal is organized into six integrated projects including two junior investigator projects and three pilot projects. The LEAD project (ROSES) includes the family development and screening for linkage to LOAD, as well as experiments designed to test chromosome 21 specific gene expression differences in EOAD and control brain regions. Junior investigator Project 1 (CLARK) describes the detailed plan for continued and expanded clinical ascertainment and development of LOAD and EOAD families. Junior investigator Project 2 (ALBERTS) describes brain region specific subtraction hybridization experiments in LOAD. Pilot Project 1 (BREITNER) develops twin studies that can provide additional families of interest for gene mapping. Pilot Project 2 (DAWSON) develops the sib-pair methodology to be applied to late onset families in which the DNA of several of the affected individuals are unavailable but whose genotype can be inferred from family data. Pilot Project 3 (BARTLETT) uses powerful new methods of genomic analyses to develop closer, flanking markers for EOAD and to define the genomic limits for subtraction hybridization strategies.